A Deficiency of Ceramide Biosynthesis Causes Cerebellar Purkinje Cell Neurodegeneration and Lipofuscin Accumulation

English version České info

Sphingolipids, lipids with a common sphingoid base (also termed long chain base) backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid changes in these diseases are pathological events or homeostatic responses. Furthermore, how changes in sphingolipid homeostasis shape the progression of aging and neurodegeneration remains to be clarified. We identified two mouse strains, flincher (fln) and toppler (to), with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration. Positional cloning demonstrated that these mutations reside in the Lass1 gene. Lass1 encodes (dihydro)ceramide synthase 1 (CerS1), which is highly expressed in neurons. Both fln and to mutations caused complete loss of CerS1 catalytic activity, which resulted in a reduction in sphingolipid biosynthesis in the brain and dramatic changes in steady-state levels of sphingolipids and sphingoid bases. In addition to Purkinje cell death, deficiency of CerS1 function also induced accumulation of lipofuscin with ubiquitylated proteins in many brain regions. Our results demonstrate clearly that ceramide biosynthesis deficiency can cause neurodegeneration and suggest a novel mechanism of lipofuscin formation, a common phenomenon that occurs during normal aging and in some neurodegenerative diseases.

Vyšlo v časopise: A Deficiency of Ceramide Biosynthesis Causes Cerebellar Purkinje Cell Neurodegeneration and Lipofuscin Accumulation. PLoS Genet 7(5): e32767. doi:10.1371/journal.pgen.1002063
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002063

Souhrn

Zdroje

1. JungTBaderNGruneT 2007 Lipofuscin: formation, distribution, and metabolic consequences. Ann N Y Acad Sci 1119 97 111

2. SelkoeDJ 2003 Folding proteins in fatal ways. Nature 426 900 904

3. RossCAPoirierMA 2005 Opinion: What is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol 6 891 898

4. JungTCatalgolBGruneT 2009 The proteasomal system. Mol Aspects Med 30 191 296

5. Ben-DavidOFutermanAH 2010 The role of the ceramide acyl chain length in neurodegeneration: involvement of ceramide synthases. Neuromolecular Med 12 341 350

6. CutlerRGKellyJStorieKPedersenWATammaraA 2004 Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc Natl Acad Sci U S A 101 2070 2075

7. HannunYAObeidLM 2008 Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9 139 150

8. LahiriSFutermanAH 2007 The metabolism and function of sphingolipids and glycosphingolipids. Cell Mol Life Sci 64 2270 2284

9. MielkeMMLyketsosCG 2010 Alterations of the sphingolipid pathway in Alzheimer's disease: new biomarkers and treatment targets? Neuromolecular Med 12 331 340

10. WangGSilvaJDasguptaSBieberichE 2008 Long-chain ceramide is elevated in presenilin 1 (PS1M146V) mouse brain and induces apoptosis in PS1 astrocytes. Glia 56 449 456

11. HaugheyNJCutlerRGTamaraAMcArthurJCVargasDL 2004 Perturbation of sphingolipid metabolism and ceramide production in HIV-dementia. Ann Neurol 55 257 267

12. HermanssonMKakelaRBerghallMLehesjokiAESomerharjuP 2005 Mass spectrometric analysis reveals changes in phospholipid, neutral sphingolipid and sulfatide molecular species in progressive epilepsy with mental retardation, EPMR, brain: a case study. J Neurochem 95 609 617

13. PiccininiMScandroglioFPrioniSBuccinnaBLobertoN 2010 Deregulated sphingolipid metabolism and membrane organization in neurodegenerative disorders. Mol Neurobiol 41 314 340

14. LwinAOrviskyEGoker-AlpanOLaMarcaMESidranskyE 2004 Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 81 70 73

15. MaglioneVMarchiPDi PardoALingrellSHorkeyM 2010 Impaired ganglioside metabolism in Huntington's disease and neuroprotective role of GM1. J Neurosci 30 4072 4080

16. SabourdyFKedjouarBSorliSCColieSMilhasD 2008 Functions of sphingolipid metabolism in mammals–lessons from genetic defects. Biochim Biophys Acta 1781 145 183

17. ImgrundSHartmannDFarwanahHEckhardtMSandhoffR 2009 Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J Biol Chem 284 33549 33560

18. LaviadELAlbeeLPankova-KholmyanskyIEpsteinSParkH 2008 Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J Biol Chem 283 5677 5684

19. BeckerIWang-EckhardtLYaghootfamAGieselmannVEckhardtM 2008 Differential expression of (dihydro)ceramide synthases in mouse brain: oligodendrocyte-specific expression of CerS2/Lass2. Histochem Cell Biol 129 233 241

20. LeeSJ 1991 Expression of growth/differentiation factor 1 in the nervous system: conservation of a bicistronic structure. Proc Natl Acad Sci U S A 88 4250 4254

21. DuchalaCSShickHEGarciaJDeweeseDMSunX 2004 The toppler mouse: a novel mutant exhibiting loss of Purkinje cells. J Comp Neurol 476 113 129

22. Pewzner-JungYBen-DorSFutermanAH 2006 When do Lasses (longevity assurance genes) become CerS (ceramide synthases)?: Insights into the regulation of ceramide synthesis. J Biol Chem 281 25001 25005

23. RiebelingCAllegoodJCWangEMerrillAHJrFutermanAH 2003 Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors. J Biol Chem 278 43452 43459

24. VenkataramanKRiebelingCBodennecJRiezmanHAllegoodJC 2002 Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells. J Biol Chem 277 35642 35649

25. MizutaniYKiharaAIgarashiY 2005 Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J 390 263 271

26. SpassievaSSeoJGJiangJCBielawskiJAlvarez-VasquezF 2006 Necessary role for the Lag1p motif in (dihydro)ceramide synthase activity. J Biol Chem 281 33931 33938

27. SulzerDMosharovETalloczyZZuccaFASimonJD 2008 Neuronal pigmented autophagic vacuoles: lipofuscin, neuromelanin, and ceroid as macroautophagic responses during aging and disease. J Neurochem 106 24 36

28. JalankoABraulkeT 2009 Neuronal ceroid lipofuscinoses. Biochim Biophys Acta 1793 697 709

29. HeineCKochBStorchSKohlschutterAPalmerDN 2004 Defective endoplasmic reticulum-resident membrane protein CLN6 affects lysosomal degradation of endocytosed arylsulfatase A. J Biol Chem 279 22347 22352

30. MoleSEMichauxGCodlinSWheelerRBSharpJD 2004 CLN6, which is associated with a lysosomal storage disease, is an endoplasmic reticulum protein. Exp Cell Res 298 399 406

31. LonkaLKyttalaARantaSJalankoALehesjokiAE 2000 The neuronal ceroid lipofuscinosis CLN8 membrane protein is a resident of the endoplasmic reticulum. Hum Mol Genet 9 1691 1697

32. SchulzAMousallemTVenkataramaniMPersaud-SawinDAZuckerA 2006 The CLN9 protein, a regulator of dihydroceramide synthase. J Biol Chem 281 2784 2794

33. TahaTAMullenTDObeidLM 2006 A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death. Biochim Biophys Acta 1758 2027 2036

34. OsuchowskiMFEdwardsGLSharmaRP 2005 Fumonisin B1-induced neurodegeneration in mice after intracerebroventricular infusion is concurrent with disruption of sphingolipid metabolism and activation of proinflammatory signaling. Neurotoxicology 26 211 221

35. MenuzVHowellKSGentinaSEpsteinSRiezmanI 2009 Protection of C. elegans from anoxia by HYL-2 ceramide synthase. Science 324 381 384

36. FuruyaSOnoKHirabayashiY 1995 Sphingolipid biosynthesis is necessary for dendrite growth and survival of cerebellar Purkinje cells in culture. J Neurochem 65 1551 1561

37. SchwarzAFutermanAH 1998 Inhibition of sphingolipid synthesis, but not degradation, alters the rate of dendrite growth in cultured hippocampal neurons. Brain Res Dev Brain Res 108 125 130

38. Takemoto-KimuraSAgeta-IshiharaNNonakaMAdachi-MorishimaAManoT 2007 Regulation of dendritogenesis via a lipid-raft-associated Ca2+/calmodulin-dependent protein kinase CLICK-III/CaMKIgamma. Neuron 54 755 770

39. HeringHLinCCShengM 2003 Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability. J Neurosci 23 3262 3271

40. LinRCMatesicDFConnorJA 1997 The role of dendritic dysfunction in neurodegeneration. Ann N Y Acad Sci 825 134 145

41. EdingerAL 2009 Starvation in the midst of plenty: making sense of ceramide-induced autophagy by analysing nutrient transporter expression. Biochem Soc Trans 37 253 258

42. SpassievaSDMullenTDTownsendDMObeidLM 2009 Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response. Biochem J 424 273 283

43. CostantiniCKolasaniRMPuglielliL 2005 Ceramide and cholesterol: possible connections between normal aging of the brain and Alzheimer's disease. Just hypotheses or molecular pathways to be identified? Alzheimers Dement 1 43 50

44. D'MelloNPChildressAMFranklinDSKaleSPPinswasdiC 1994 Cloning and characterization of LAG1, a longevity-assurance gene in yeast. J Biol Chem 269 15451 15459

45. JazwinskiSMKimSDaiJLiLBiX 2010 HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging. Aging Cell 9 698 708

46. MuckeLMasliahEJohnsonWBRuppeMDAlfordM 1994 Synaptotrophic effects of human amyloid beta protein precursors in the cortex of transgenic mice. Brain Res 666 151 167

47. ZhaoLLongo-GuessCHarrisBSLeeJWAckermanSL 2005 Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Nat Genet 37 974 979

48. ZhaoLRosalesCSeburnKRonDAckermanSL 2010 Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjogren syndrome. Hum Mol Genet 19 25 35

49. AckermanSLKozakLPPrzyborskiSARundLABoyerBB 1997 The mouse rostral cerebellar malformation gene encodes an UNC-5-like protein. Nature 386 838 842

50. BechtoldLS 2000 Ultrastructural Evaluation of Mouse Mutations. SundbergJDawnalynB Systematic Approach to Evaluation of Mouse Mutations CRC Press

51. BielawskiJPierceJSSniderJRembiesaBSzulcZM 2009 Comprehensive quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry. Methods Mol Biol 579 443 467

52. SambrookJFritschEFManiatisT 1989 Molecular Cloning: a laboratory manual Cold Spring Harbor Laboratory Press

54. Kageyama-YaharaNRiezmanH 2006 Transmembrane topology of ceramide synthase in yeast. Biochem J 398 585 593